Mackay Helen J, Eisenhauer Elizabeth A, Kamel-Reid Suzanne, Tsao Ming, Clarke Blaise, Karakasis Katherine, Werner Henrica M J, Trovik Jone, Akslen Lars A, Salvesen Helga B, Tu Dongsheng, Oza Amit M
Princess Margaret Hospital, Toronto, Ontario, Canada.
Cancer. 2014 Feb 15;120(4):603-10. doi: 10.1002/cncr.28414. Epub 2013 Oct 25.
Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is of increasing interest as a therapeutic strategy in many tumors. The aim of this study was to identify molecular markers associated with mTOR inhibitor activity in women with metastatic endometrial cancer.
Archival tumor samples were collected from 94 women with recurrent or metastatic endometrial cancer who participated in 3 National Cancer Insitute of Canada Clinical Trials Group phase 2 trials investigating single-agent mTOR inhibitors: IND160A and IND160B (temsirolimus) and IND192 (ridaforolimus). Analyses included mutational profiling using the OncoCarta Panel version 1.0 and immunohistochemical expression of the tumor suppressor gene PTEN (phosphatase and tensin homologue) and stathmin, a marker of PI3K activation. Associations between biomarker results and clinical outcomes were assessed.
Mutations were found in 32 of 73 analyzed tumors, PIK3CA (21 patients) was the most common mutated gene. Co-mutations were seen in 8 tumors, most frequently KRAS and PIK3CA (4 cases). PTEN loss was observed in 46 of 85 samples analyzed and increased stathmin expression was observed in 15 of 65 analyzed samples. No correlation was observed between biomarkers and response or progression. In patients taking concurrent metformin, there was a trend toward lower progression, of 11.8% versus 32.5% (P = .14).
No predictive biomarker or combination of biomarkers for mTOR inhibitor activity were identified in this study. Restriction and enrichment of study entry, especially based on archival tumor tissue, should be undertaken with caution in trials using these agents.
在许多肿瘤中，将磷脂酰肌醇3激酶（PI3K）/AKT/雷帕霉素哺乳动物靶点（mTOR）通路作为一种治疗策略越来越受到关注。本研究的目的是在转移性子宫内膜癌女性患者中确定与mTOR抑制剂活性相关的分子标志物。
从94例复发性或转移性子宫内膜癌女性患者中收集存档肿瘤样本，这些患者参与了加拿大国家癌症研究所临床试验组的3项2期试验，研究单药mTOR抑制剂：IND160A和IND160B（替西罗莫司）以及IND192（瑞达法莫司）。分析包括使用OncoCarta Panel 1.0版进行突变分析，以及肿瘤抑制基因PTEN（磷酸酶和张力蛋白同源物）和作为PI3K激活标志物的微管相关蛋白2的免疫组化表达。评估生物标志物结果与临床结局之间的关联。
在73例分析的肿瘤中有32例发现突变，PIK3CA（21例患者）是最常见的突变基因。在8例肿瘤中发现共突变，最常见的是KRAS和PIK3CA（4例）。在85例分析样本中有46例观察到PTEN缺失，在65例分析样本中有15例观察到微管相关蛋白2表达增加。未观察到生物标志物与反应或进展之间的相关性。在同时服用二甲双胍的患者中，有疾病进展较低的趋势，分别为11.8%和32.5%（P = 0.14）。
本研究未发现mTOR抑制剂活性的预测性生物标志物或生物标志物组合。在使用这些药物的试验中，应谨慎进行研究入组的限制和富集，尤其是基于存档肿瘤组织的情况。
